Studies Towards the Total Synthesis of

Biological Active γ-Butyrolactones

Dissertation

zur Erlangung des Doktorgrades der Naturwissenschaften

Dr. rer. nat. an der Fakultät für Chemie und Pharmazie

der Universität Regensburg

vorgelegt von

Andreas Schall

aus

Runding

Regensburg 2007

2

Die Arbeit wurde angeleitet von: Prof. Dr. O. Reiser

Promotionsgesuch eingereicht am: 25. Mai 2007

Promotionskolloquium am: 26. Juni 2007

Prüfungsausschuss: Vorsitz: Prof. Dr. H. Krienke

1. Gutachter: Prof. Dr. O. Reiser

2. Gutachter: Prof. Dr. B. König

3. Prüfer: Prof. Dr. S. Elz

3

Der experimentelle Teil der vorliegenden Arbeit wurde unter der Leitung von Herrn Prof. Dr.

Oliver Reiser in der Zeit von Oktober 2003 bis Mai 2007 am Institut für Organische Chemie

der Universität Regensburg sowie in der Gruppe von Prof. Dr. Paul Hanson, University of

Kansas, angefertigt,

Herrn Prof. Dr. Oliver Reiser möchte ich herzlich für die Überlassung des äußerst

interessanten Themas, die anregenden Diskussionen und seine stete Unterstützung während

der Durchführung dieser Arbeit danken.

4

5

for my family…

“If you want to build a ship, don't drum up the men to gather wood,

divide the work and give orders. Instead, teach them to yearn for the vast and endless sea.”

Antoine de Saint-Exupéry (1900 - 1944)

Table of Content

6

Table of Content

1. APPROACHES TO THE TOTAL SYNTHESIS OF BIOLOGICAL ACTIVE

GUAIANOLIDES WITH A TRANS-ANNULATED LACTONE MOIETY 8

1.1 INTRODUCTION 8 1.2 BIOSYNTHESIS OF GUAIANOLIDES 10 1.3 RACEMIC APPROACHES TOWARDS GUAIANOLIDES 15 1.4 STEREOSELECTIVE TOTAL SYNTHESIS OF GUAIANOLIDES 21 1.5 HEMI-SYNTHESIS STARTING FROM SANTONIN 28 1.6 CONCLUSIONS 35

2. AIM OF THIS WORK 36

2.1 CYNAROPICRIN - THE HERB PRINCIPLE OF ARTICHOKE 36 2.2 IXERIN Y - A GUAIANOLIDE SESQUITERPENE LACTONE GLUCOSIDE 37 2.3 RETROSYNTHETIC ANALYSIS OF THE TARGET COMPOUNDS 38

3. SYNTHESIS OF CHIRAL ALLYLSILANES 40

3.1 SYNTHESIS OF THE ENANTIOMERIC PURE CYCLOPENTENONE 41 3.2 SYNTHESIS OF THE CHIRAL ALLYLSILANES 44

4. SYNTHESIS OF THE CYCLOPROPYLCARBALDEHYDE 47

5. FORMATION OF THE ANTI-SUBSTITUTED LACTONE ALDEHYDE 50

6. INVESTIGATIONS TOWARDS 5,6,5-RING SYSTEMS 53

6.1 INTRAMOLECULAR CARBONYL-ENE REACTION 53 6.2 SMI2-PROMOTED RADICAL CYCLIZATION 55

7. INVESTIGATIONS TOWARDS THE GUAIANOLIDE CORE SKELETON 56

7.1 RADICAL CYCLIZATION APPROACH 56 7.2 RING CLOSING METATHESIS APPROACH 59 7.3 SYNTHESIS OF A 3X3 SCAFFOLD LIBRARY 65

Table of Content

7

8. TOWARDS CYNAROPICRIN AND IXERIN Y 73

8.1 INVERSION OF THE C4-STEREOCENTER 73 8.2 INVESTIGATIONS ON EPOXIDATIONS 75 8.3 TAMAO-FLEMING OXIDATION 76 8.4 OXIDATION AT THE C8-POSITION 81 8.5 ELIMINATION REACTIONS 82

9. STEREOSELECTIVE SYNTHESIS OF SMALL MOLECULE HAT INHIBITORS 88

10. SUMMARY 94

11. EXPERIMENTAL PART 97

11.1 GENERAL 97 11.2 ABBREVIATIONS 99 11.3 SYNTHESIS OF CHIRAL ALLYLSILANES 100 11.4 SYNTHESIS OF THE CYCLOPROPYLCARBALDEHYDE 115 11.5 FORMATION OF THE ANTI-SUBSTITUTED LACTONE ALDEHYDE 119 11.6 RADICAL CYCLIZATION 121 11.7 PRECURSORS FOR RING CLOSING METATHESIS 124 11.8 RING CLOSING METATHESIS 131 11.9 SYNTHESIS OF A 3X3 SCAFFOLD LIBRARY 137 11.10 TOWARDS CYNAROPICRIN AND IXERIN Y 150 11.11 STEREOSELECTIVE SYNTHESIS OF GCN5 INHIBITORS 165

12. APPENDIX 170

12.1 NMR - SPECTRA 170 12.2 X-RAY DATA 231

13. REFERENCES 244

Introduction

8

1. Approaches to the total synthesis of biological active guaianolides with a trans-annulated lactone moiety

1.1 Introduction

Guaianolides, consisting of a tricyclic 5,7,5-ring system represent a large subgroup of

naturally occurring sesquiterpene lactones exhibiting significant biological activity.[1,2] Plants

containing such compounds as the active principles have been used in traditional medicine

throughout history for treating conditions ranging from rheumatic pains, increase of bile

production to pulmonary disorders.

Figure 1. Skeletal relationships.

As the name itself indicates, the core structure of the guaianolides is derived from Guaiane, a

natural product with a cis-fused 5,7-bicyclic hydroazulene ring-system (Figure 1). With only a

few exceptions the hydroazulene core is also cis-fused in the 5,7,5-tricyclic carbon skeleton,

while the γ-butyrolactone ring is trans-annulated in approximately 85% of all known

guaianolides.[3]

This interesting class of natural products shows a broad range of biological activity (Figure 2)

stimulating the development of research towards their total synthesis. Although several

strategies especially towards monocyclic γ-butyrolactones are reported to date,[4-10] only a few

groups succeeded in the total synthesis of guaianolides.[10-14]

Introduction

9

H

OR3

OAc

O

R1OHOHO

OH

R2

Thapsigargins (6)

DehydrocostusLactone (2)

OHH

O

H

H OHH

OO

H

Cladantholide (3)

H

Estafiatin (4)

O

O

HHO

H

H

Eremanthin (5)

OHH

O

H

H

isolated fromcostus root (mokko)antimycobacterial activity(MIC = 2-16 µg/ml)

isolated fromEremanthus elaeagnusschistosomicidal activity

isolated fromCladanthus arabicusantifeedant activity

isolated fromThapsia garganicapotent Ca-modulatingproperties

O

HO

H

H

O

Arglabin (1)isolated fromArtemisia glabellafarnesyl transferaseinhibitor(IC50 = 0.9-5.0 µg/ml)

isolated fromArtemisia mexicanaantihelminthic activity

Figure 2. Some guaianolides, representing the structural diversity of this class of compounds.

The structure-activity relationship (SAR) of α-methylene sesquiterpene lactones was

intensively studied.[15-20] It was shown that these compounds can react by conjugate addition

of various biological nucleophiles such as cystein or thiol-containing enzymes (E-SH)

(Scheme 1). Consequently, α-methylene sesquiterpene lactones are good alkylation agents

manifesting their biological activity but also their cytotoxicity.

Scheme 1. Michael addition on α-methylene sesquiterpene lactones.

There is further evidence, that compounds of this type inhibit cellular enzyme activity and do

not show DNA-alkylating properties.[18,21-26] Furthermore it is assumed that the residual

substitution pattern of the guaianolides determines the specificity and the resulting biological

activity.[11]

Introduction

10

1.2 Biosynthesis of guaianolides

1.2.1 The mevalonate pathway

Since ancient times various oils with intensive and mostly delightful fragrances were

extracted from numerous plants. In the beginning direct distillation and later on steam

distillation were common techniques to afford the essential oils, which mainly consisted of

terpenes. Until now more than 30,000 terpenes from all sources have been identified, making

them a large and structurally highly diverse family of natural products. It was early

recognized that terpenes are formally derived from C5-isoprene units (7), but that isoprene (8)

itself, a metabolite produced naturally, is not involved in their formation (Figure 3).

Figure 3. Comparsion of C5-units.

The biochemically active isoprene units are isopentenyl-pyrophosphate (IPP, 9) and

γ,γ-dimethylallyl-pyrophosphate (DMAPP, 10). These important precursors are formed via

certain biochemical pathways that have been extensively studied over the last 50 years leading

to the generally accepted mevalonate (MVA) biosynthesis pathway of terpenes in

organisms.[27-30] More recently a second biosynthetic route was discovered in plants also

leading to IPP (9) and DMAPP (10) as the final products.[30-32] This so called mevalonate

independent pathway or methylerythritol-phosphate pathway (MEP) is only found in a few

plants and microorganisms. It was also recognized that the MVA-pathway is located in the

cytosol and the MEP-pathway takes place in the plastids (chloroplasts, leukoplasts, etc.).

Furthermore, in organisms equipped with both pathways, a limited exchange of intermediates

between MVA and MEP also appears. This may explain why the MEP pathway was

completely overlooked until labeling experiments revealed its existence.[33-36]

The biosynthesis in the cytosol starts with the assembly of three molecules of activated acetic

acid (acetyl-CoA) (11) by an initial Claisen-condensation and a subsequent aldol reaction to

give β-hydroxy-β-methyl-glutaryl-CoA (13) (Scheme 2).

Introduction

11

CoAS CH3

O CH3

OCoAS CoAS

O CH3

O

O

SCoA

-HSCOA+H2O

O

SCoA

HO CH3HO2C OH

HO CH3HO2C

(NADPH + H+)

-HSCoA

+

11 11 12

11

13Mevalonate (14)

ATPOPP

HO CH3HO2C

-CO2

-H2O

OPP OPP

IPP (9) DMAPP (10)

15

Scheme 2. MVA pathway for the biosynthesis of IPP (9) and DMAPP (10).

Reduction with NADPH+H+ releases mevalonic acid (Mevalonate, MVA, 14), which is then

activated by means of ATP to the pyrophosphomevalonate (15). Decarboxylation and

elimination leads to isopentenyl-pyrophosphate (IPP, 9), further isomerization of the double

bond to dimethylallylpyrophosphate (DMAPP, 10).

To construct the basic backbones of terpenes, prenyltransferases connect IPP (9) and its

isomer DMAPP (10) in a head to tail fashion (Scheme 3). In a first step DMAPP (10) is

therefore ionized to an allylic cation 16, to which the double bond of IPP (9) can add resulting

in a tertiary cation 17. Subsequent stereoselective loss of a proton introduces selectively a new

trans substituted double bond and releases geranylpyrophosphate (GPP, 18), a fundamental

precursor for the biosynthesis of monoterpenes (e.g. menthol).

Introduction

12

IPP (9)

OPPOPP

HSHR

electrophilicaddition

OPPHSHR

stereospecificloss of proton

OPP

GPP (18)monoterpenes (C10)

DMAPP (10) 16

17

OPPHSHR

1. electrophilic addition

OPP

FPP (19)

sesquiterpenes (C15),e.g. Guaianolides

IPP (9)

2. stereospecific lossof proton

Scheme 3. Biosynthesis of GPP (18) and FPP (19).

For the biosynthesis of sesquiterpenes the C10-skeleton of GPP (18) has to be extended by

addition of a further C5-IPP (9) unit according to the isoprene rule[37-39] ((C5)n, n = 3 for

sesquiterpenes) which was first discovered by Otto Wallach in 1887 but largely ignored until

Leopold Ruzicka recognized its general significance. Repeating the electrophilic addition of

IPP (9) and stereospecific elimination (Scheme 3) gives rise to farnesylpyrophosphate

(FPP, 19), the precursor for linear and cyclic sesquiterpenes and sesquiterpene lactones.

1.2.2 Biosynthesis of guaianolides

The further assembly of guaianolides used in nature has been intensively investigated by

de Kraker et al. based on the biosynthetic route of sesquiterpene lactones in chicory which is

reasonable to assume to be also valid for other plant species (Scheme 4).[40-43] According to

these studies, cyclization of FPP (19) yields (+)-Germacrene A (20). Because of the double

bond configuration in FPP (19) two (E)-substituted double bonds are incorporated within the

10-membered ring system of 20.

Oxidation of the isopropenyl side chain by (+)-Germacrene A hydroxylase to the primary

alcohol 21 and further oxidations by NAD(P)+-dependent dehydrogenases afford

Introduction

13

Germacrene acid (23). It was further demonstrated that hydroxylation on the C6-position and

subsequent lactonization yields (+)-Costunolide (25).

This intermediate is seen as a branching point in the biosynthesis of sesquiterpene lactones,

because here the pathways for the formation of guaianolides, eudesmanolides and

germacranolides are considered to divide.

PPO

FPP (19)

PPO- NADPHO2

NADP+H2O

(+)-Germacrene A (20) NAD(P)+

NAD(P)H

NAD(P)+

NAD(P)H

HO2C

Germacrene acid (23)

21

22

NADPHO2

NADP+H2O

HO2CHOO

O

H2O

24(+)-Costunolide (25)

Guaianolides, e.g. Arglabin

Eudesmanolides, e.g. Santonin

Germacranolides, e.g. Parthenolide

6 6

H

H

H H

OHC

H

HOH2C

HHH

3

Scheme 4. Biosynthesis of (+)-Costunolide (25).

Quite a number of stereospecific biomimetic transformations of germacranolides and their

derivatives into eudesmanolides and guaianolides have been reported in literature.[44-52] Based

upon these studies it is postulated that the second cyclization of germacranolides towards the

guaianolide skeleton is directed by epoxidations or hydroxylations of the costunolide

skeleton 25. Enzymatic epoxidation on C4-C5 position directly affords Parthenolide (26)

(Scheme 5). This interesting germacranolide is a highly active antimigraine agent isolated

from feverfew and magnolia and also shows anti-inflammatory and anti-tumor activities.[53-55]

Trans-annular cyclization of the strained ring system in 26 and subsequent elimination

completes the guaianolide skeleton 27.[56]

Introduction

14

Scheme 5. Guaianolides (27) via cyclizations starting from (+)-Costunolide (25).

In addition to the above described route also an alternative pathway is proposed: Enzymatic

introduction of a hydroxy group at C3-position in (+)-Costunolide (25) affords 28.

Subsequent dehydration and cyclization also leads to the guaianolide skeleton 27.[43]

Further oxidation steps on the 5,7,5-membered ringsystem of 27 introduce many different

functionalities: Epoxides (e.g. found in Arglabin (1) or Estafiatin (4)) or the introduction of

hydroxy groups (see Thapsigargins (6)) on various positions contributes to the diversity and

complexity of this interesting and biologically important class of natural products.

Esterification or glycosylation[57] of the later also broadens the structural variety of the

guaianolides.

In summary, nature has proven a tremendous creativity in the construction of the guaianolides

with respect to their structures and biological functions. For an organic chemist now the

question arises how to find synthetic entries towards these natural products. Even with

modern state of the art techniques in organic synthesis at hand, the complexity of the core-

structure and the high substitution pattern still makes the class of the guaianolides a

challenging and exciting target.

Introduction

15

1.3 Racemic approaches towards guaianolides

1.3.1 Total synthesis of (±)-Compressanolide and (±)-Estafiatin

Although there are some reports in literature dealing with the synthesis of pseudo-

guaianolides[1] or of guaianolide related compounds,[58-61] to the best of our knowledge the

first total synthesis of a guaianolide with a trans-annulated lactone moiety was reported by

Vandewalle et al.[62-64] in 1982. On the basis of a novel, flexible and convergent route towards

substituted hydroazulenes the total synthesis of various sesquiterpene lactones has been

achieved.[65]

As the starting point the photochemical addition of 1,2-bis[trimethylsiloxy]-cyclopentene (29)

to cyclopentenone (30) affords the 5,4,5-membered ring system (±)-31 as a single

diastereomer, in which the five-membered rings are anti-oriented to each other (Scheme 6).

OR

OR

h

O

OO

OHH

ORRO

HH

OHHO

1. Ph3P=CH2

Pb(OAc)4 p-TsOH,O O

O O

O

2. HCl

85%71%

74%

65%

10

[2+2]

29 30 (±)-31

(±)-32 (±)-33 (±)-34

RO

ROH

H O

R = TMS

Scheme 6. Synthesis of key intermediate (±)-34.

Subsequent Wittig-reaction and TMS-deprotection set the stage for ring expansion by

oxidative cleavage of the diol (±)-32, giving rise to (±)-33 in which the exo-methylene double

bond had concurrently migrated in conjugation to the carbonyl group. Acid catalyzed

acetalization chemoselectively protected the more reactive carbonyl group on C-10 to afford

the racemic key intermediate (±)-34, which allowed access to a number of different

sesquiterpene lactones.

With the substituted hydroazulene (±)-34 in hands the group of Vandewalle started out for the

total synthesis of (±)-Compressanolide (44),[62] a guaianolide first isolated from Michelia

compressa.[66] Furthermore a small variation of this route allowed the synthesis of

Introduction

16

(±)-Estafiatin (4),[62,64] a natural product first isolated by Romo and co-workers from

Artemisia mexicana (Willd).[67]

The opening step entails the epoxidation of the double bond in the 5-membered ring of (±)-34

(Scheme 7, top). Controlled by steric hindrance (shielding of the β-face by the bulky ketal

protecting group) the bulkiest reagent gave the best selectivity of 6:1 for the desired

α-epoxide (±)-35.

In contrast, epoxidation of the key intermediate (±)-34 using H2O2 afforded the epoxide in

better yield and a 1:9 ratio, this time approaching from the β-face (Scheme 7, bottom) forming

the now desired trans-fused 5,7-membered ring system (±)-36.

Triton B,

OOHPh1. LDA,

2. separate3. DBU40%

78%

Br

(±)-34

OO

O

OO

HO

O

OH

7

(±)-35 (±)-37

7

2:1

1. H2O22. separate

O O

HO

O

7

O O

HO

O

71. LDA,

Br

70%

= 6:1

60%

(±)-36 (±)-38

4:1

=1:9

Scheme 7. Stereoselective epoxidation and alkylation.

The next key step in the synthesis is the selective introduction of the prenyl-sidechain at the

C7-position which is later on used for the formation of the lactone moiety. Attempts to

introduce this arm by kinetic controlled deprotonation/alkylation already in the key

intermediate (±)-34 failed, but alkylation of epoxide (±)-35 afforded the desired product

(±)-37 in a 2:1 ratio (β:α). Base induced equilibration of the undesired epimer led again to an

approx. 1:1 ratio, providing the possibility to recycle the unwanted epimer. Alkylation of

(±)-36 on C-7 also introduced the prenyl-sidechain and afforded (±)-38 in a 4:1 ratio.

The selective reductive opening of the epoxide in (±)-37 is the next crucial reaction, installing

three stereocenters present in (±)-Compressanolide (44) within one step. This complex

sequence starts with a reductive cleavage of the epoxide present in (±)-37 and a fast

protonation of the resulting enolate (±)-39 (Scheme 8).

Introduction

17

H+

R =

OO

HO

OR

O

O

HO

OR

HH

O

HO

HO

OR

H

(±)-37

(±)-39 (±)-40

1. Li, NH3, NH4Cl

2. repeat57%

HO

HO

HO

O

H

(±)-41

7

Scheme 8. Stereoselective reduction sequence.

Intramolecular tautomerization to ketone (±)-40 by intramolecular proton transfer from the

near by hydroxy group leads to a less strained cis-annulated hydroazulene ring system.

Subsequent in situ reduction gives rise to the more stable equatorial alcohol (±)-41, trans to

the vicinal prenyl-sidechain at the C7-position.

The trans-lactone moiety in (±)-42 is obtained by ozonolysis and Jones-oxidation of the

prenyl-side chain completing the guaianolide skeleton (Scheme 9). Acid deprotects the

masked ketone and a Wittig-reaction introduces the exo-methylenic double bond at the

C10-position of (±)-43, a very common structural feature of sesquiterpene lactones.

1. O3, DMS2. Jones 1. Ph3P=CH2

1. LDA, MeI

2. LDA, NH4Cl

1:3(±)-Compressanolide (44)

79%

44%

O

OH

HO

HO

H

H

O

OH

HHO

H

H

(±)-42

(±)-41 O

OTMS

HHO

H

H

(±)-43

3. HCl 2. TMSCl

81 %

10

Scheme 9. Final steps towards (±)-Compressanolide (44).

The resulting tertiary alcohol was protected, before α-methylation unfortunately afforded a

mixture of 1:4 for the undesired isomer of (±)-44. Equilibration by kinetic protonation of the

enolate improved the ratio only slightly to 1:3 towards (±)-Compressanolide (44).

Introduction

18

Applying the stereoselective reduction on (±)-38 as described above (Scheme 8) and sub-

sequent oxidation gave rise to the all-trans substituted 5,7,5-ring system (±)-45 (Scheme 10).

1. Li, NH3,NH4Cl

2. O3, DMS

3:1 endo:exo

1. HCl2. separate

3. Ph3P=CH2

1. LDA, CH2O2. MsCl

3. DBU4. mCPBA

(±)-Estafiatin (4)(4.3% overall)

56%

3. Jones

Burgess

57%61%

O

O

HHO

H

HOHH

O

H

H

OHH

O

H

H

OO

OHH

O

H

H

OO

OH

75%

(±)-45(±)-46

(±)-47

(±)-38

Scheme 10. Finals steps in the synthesis of (±)-Estafiatin (4).

The regioselective elimination of the tertiary alcohol present in (±)-45 proved to be difficult:

As classical methods for the dehydration failed, only the application of Burgess-reagent

resulted in a 3:1 endo:exo elimination towards (±)-46. Acidic deprotection of the ketal also is

accompanied with an equilibration of the resulting ketone to 3:1 for the desired more stable

cis-connected endocyclic alkene (±)-47. Subsequent Wittig-olefination and α-methylenation

followed by epoxidation of the more reactive trisubstituted endocyclic double bond finally

afforded (±)-Estafiatin (4) in 4.3% overall yield.

Introduction

19

1.3.2 Total synthesis of (±)-Dehydrocostus Lactone and (±)-Grosshemin

Four years later Rigby et al.[68,69] reported the racemic synthesis of three further guaianolides

((±)-Dehydrocostus Lactone (2) (IC50 = 14 µM, CTL cells[70]), (±)-Estafiatin (4) and

(±)-Grosshemin (62) starting from commercially available 2,4,6-cycloheptatrienone

(Tropone) (48). Similar to the Vandewalle-approach described above, the first target was also

the construction of the hydroazulene core. Utilizing the 7-membered ringsystem already

present in Tropone (48), 1,8-addition of appropriate nucleophiles afforded the alkylated

products 49 and 50, which were further converted into the aldehyde 51 and the

diazocompound 52, respectively (Scheme 11).

O

BrMg O

OOMe

CHO

Tropone (48)OLi

OtBu

O OPivO

N2

O

OtBu

O

O O

3 steps

5 steps

49

50

51

52

96%

90%

73%

70%

Scheme 11. Functionalization of Tropone (48) by Rigby et al.

The required cis-fused hydroazulene ring system is then formed via a Lewis-acid mediated

cyclization on 51 and subsequent reductive opening of the resulting epoxide (±)-53 releasing

the next key-intermediate (±)-54 in the synthesis of (±)-Estafiatin (4) (Scheme 12, top).

BF3 OEt2

Cu/CuSO4

H

H

O

OMe

O

OPivHH

1. Ac2O,BF3 OEt2

OAc

OPivH

HAcO

MEMO

H

H

OMe

1. Li, MeNH2

2. MEMCl51

52

(±)-53 (±)-54

(±)-55 (±)-56

75% 93%

92%

80%

Scheme 12. Formation of cis-fused hydroazulene systems.

Introduction

20

Alternatively an intramolecular cyclopropanation in 52 gives rise to the tricyclic system

(±)-55 which is then opened by a Lewis-acid mediated homoconjugate addition reaction

releasing the intermediate (±)-56 for the synthesis of (±)-Grosshemin (62) (Scheme 12,

bottom).

To introduce the trans-fused lactone moiety, the double bond in (±)-54 was first selectively

epoxidized (approach of peracid from the less hindered upper face) and then the epoxide was

opened with the appropriate lithium-organyle closing the ring to lactone (±)-57 (Scheme 13).

Functional group transformation leads in 4 steps to the diene (±)-58.

1. mCPBA

2.

OLi

OLi OHH

MEMO

O

OMe

1. LDA,Me2NCH2I

2. MeI

(±)-DehydrocostusLactone (2)

(1.0% overall)

1. BF3 OEt2

2. mCPBA

(±)-Estafiatin (4)(0.3% overall)

4 steps(±)-54

H

H

OHH

OH

H

OHH

OH

H

OHH

OH

H

O

(±)-57 (±)-5842%

71% 35%

6%

Scheme 13. Final steps towards (±)-Dehydrocostus Lactone (2) and (±)-Estafiatin (4).

The still missing α-exo-methylenic group is introduced via a Mannich-type reaction to yield

(±)-Dehydrocostus Lactone (2) in 1.0% overall yield. The structural closely related

(±)-Estafiatin (4) was then obtained in 0.3% overall yield by selective isomerization of the

double bond present in (±)-2 towards the more stable tetrasubstitution and subsequent regio-

and stereoselective epoxidation.

Using the hydroazulene key intermediate (±)-56 Rigby and coworkers started out for the

synthesis of (±)-Grosshemin (62), first isolated by Rybalko et al. from Grossheimia

macrocephala.[71] The methyl group present in (±)-Grosshemin (62) was selectively

introduced via alkylation by methyliodid approaching over the less hindered upper face of

(±)-56 (Scheme 14).

Introduction

21

1. MeLi, MeI

2. TMSOTf,(TMSOCH2)2 O

OPivH

HAcO OO

H

HHO O

1. VO(acac)2,tBuOOH

2. LiCH2CO2Li

O

HH

OO

HO

O

1. LDA,Me2NCH2I

2. MeI

3. H+HH

O

HO

O

O(±)-Grosshemin (62)

(8.6 % overall)

6 steps(±)-56

H

H

H

H

(±)-59 (±)-60

(±)-61

56%

76%

65% 71%

Scheme 14. Final steps towards (±)-Grosshemin (62).

Further six steps including functional group transformation and Wittig olefination lead to

allylalcohol (±)-60. The trans-fused lactone ring is introduced by directed epoxidation via the

allylic alcohol and subsequent epoxide opening as shown in (±)-61. Again a Mannich-type

reaction introduced the α-exo-methylene group at the lactone ring and finalized the synthesis

of (±)-Grosshemin (62) in 8.6% overall yield.

1.4 Stereoselective total synthesis of guaianolides

1.4.1 Total synthesis of (+)-Cladantholide and (-)-Estafiatin

A very elegant stereoselective approach towards two members of the guaianolide family via a

radical cyclization cascade was reported by Lee and co-workers,[72] who succeeded in the total

synthesis of (+)-Cladantholide (3) (isolated from Cladanthus arabicus (L.) Cass.)[73] and

(-)-Estafiatin (4) starting from (R)-Carvone (63).

In three steps the chlorohydrin derivative 64 was synthesized, which was subjected to a

stereoselective Favorskii-rearrangement to afford the highly substituted cyclopentane-

carboxylate 65 (Scheme 15). Three more steps were necessary to obtain the bromoacetal 66,

which was set up for a radical cyclization being initiated by AIBN/Bu3SnH under standard

high-dilution conditions. 67 was obtained in quantitative yield and perfect diastereoselectivity

with respect to the newly created stereocenters at the C7- and the C10-position.

Introduction

22

O

H3 steps

O

H

ClOTHP

H MeO2CH

OTHP

(R)-Carvone (63) 64 65

Favorskii-rearrangement

58% from 63

H

OTHPHO

Br

EtO OHH

OTHP

EtO7

10AIBN,Bu3SnH

H

H

66 67

75% 99%

3 steps

H

Scheme 15. Favorskii-rearrangement and radical cyclization.

The stereochemical outcome of this highly selective and efficient cascade can be explained by

conformational analysis of the substrate (Scheme 16): The most stable conformation of the

cyclopentane ring in 68 is represented with three substituents in equatorial positions, and the

attached sidechains are oriented chairlike.

Scheme 16. Conformational analysis of 68 and radical cyclization.

Consequently 5-exo-cyclization of the primary radical onto the opposite double bond forms

the trans cyclic acetal 69 setting the correct stereochemistry on C7. Subsequent 7-endo

cyclization affords the tertiary radical 70, while the alternative kinetically favored 6-exo

pathway was not observed. Final hydrogen addition setting the correct stereocenter at C10

must have occurred from the α-face, which is presumable sterically less hindered.

The high preference for the 7-membered ring formation by radical cyclization was also

observed by Reiser and co-workers during their investigations on model systems towards the

synthesis of bi- and tricyclic sesquiterpene lactones of the xanthanolide and guaianolide

family (Scheme 17).[74]

Introduction

23

OO

Br

CO2EtH

H

Bu3SnH/AIBN

7-endoOO

CO2EtH

H

71 72

83-95%

Scheme 17. 7-endo cyclization by Reiser et al.

To finalize the synthesis of (+)-Clandantholide (3) Lee et al. had to transform 67 to the

ketoacetal 73, in which the introduction of a hydroxy group adjacent to the ketogroup yields

α-hydroxyketone 74 (Scheme 18).

1. LDA,TMSCl

2. Dimethyl-dioxirane

1. TsNHNH2

OHH

OO

H

(+)-Cladantholide (3)H

OHH

OHMeO

H

H

O

OHH

MeO

H

H

O

67

73 74

80%

79%

OHH

OHMeO

H

H

2 steps

2. MeLi

40%

46%

2 steps

75

OHH

N

MeO O

HN

Li

Ts

H

H

76

Scheme 18. Synthesis of (+)-Cladantholide (3).

Applying the Shapiro-protocol to 74 resulted in the regioselective introduction of the C=C-

double bond to give the allylalcohol 76. It was argued, that the reaction proceeds through an

intermediate 75, in which the lithium coordinates with the first nitrogen of the hydrazone and

the adjacent hydroxy group. Consequently, excess base can only deprotonate next to the

methyl group, affording the trisubstituted double bond in 76. Finally, oxidation and

stereoselective α-methylation completed the synthesis of (+)-Cladantholide (3).

Introduction

24

H

OTHPH

O

Cl

O OHH

OTHP

O7

10

H

H

77 78

65%

65

MeO2C MeO2C ClMn(OAc)3Cu(OAc)2

86%

2 steps

OHH

OH

HMeO2C2 steps

71%

(-)-Estafiatin (4)

O

O

HHO

H

H

79

1. LiOH, CH2NMe2I

2. mCPBA54%

Scheme 19. Synthesis of (-)-Estafiatin (4).

65 has also been the starting point for the synthesis of (-)-Estafiatin (4) (Scheme 19), for

which again a radical cascade cyclization has been the key step. In difference to the reductive

conditions employed for the transformation of 66 to 67, the cyclization of 77 to 78 was carried

out under oxidative conditions, being initiated by hydrogen rather than halogen abstraction of

the α-halo-carbonyl functionality. Reductive dechlorination and dehydration proceeded

uneventfully to 79 and subsequent α-methylenation using Eschenmoser´s salt and selective

epoxidation of the endo double bond afforded (-)-Estafiatin (4).

1.4.2 Synthesis of the Thapsigargins by Ley et al.

A powerful demonstration of modern organic synthesis was shown by Ley and co-workers

with their total synthesis of the Thapsigargins (6).[75-77] Although extracts from the root of

Thapsia garganica L. were used for a long time as treatment for rheumatic pains and

pulmonary disorders, the identification and characterization of the active principles was not

reported until 1980.[78,79] The potent biological activities reach from histamine liberation[80] to

selective Ca2+-modulating properties[81-83] on subnanomolar concentrations.

The outstanding activity and the complex molecular structure consisting of a polyoxygenated

5,7,5-core structure which is further functionalized with eight stereogenic centers and up to

four different ester groups, makes this class of guaianolides to an especially challenging target

for total synthesis.

The overall strategy towards the Thapsigargins (6) was again to construct the hydroazulene

core first and subsequently functionalize it towards the target.

Introduction

25

Therefore Ley and co-workers started from (S)-Carvone (63) following a similar route as

described above for Lee et al.[72] Within five steps 80 was reached and further eight high

yielding steps lead to aldehyde 81 with already one allyl sidearm installed (Scheme 20).

Scheme 20. Ring closing metathesis as an essential key step.

The second arm for the ring closing metathesis key step was introduced using the lithium

anion of ethylvinylether. Following strictly the Felkin-Anh model diene 82 was generated as a

single diastereomer. The bicyclic hydroazulene ringsystem was then constructed by ring

closing metathesis affording 83 in high yield.

The convex half space of the double bond present in 83 is shielded by the bulky TES

protecting group and so osmylation results in good selectivity (16:1) for the concave attack

releasing 84 (Scheme 21).

Scheme 21. Facial selective osmylation.

Introduction

26

Esterification of the resulting alcohol and subsequent intramolecular Horner-Wadsworth-

Emmons reaction provided the butenolide 85 which was within 3 steps transformed into 86.

Further functionalization of 86 towards the highly oxygenated core system of the targets was

performed by selective dihydroxylation of the side chain to yield 87 (Scheme 22). The desired

trans-annulated lactone 88 was formed after selective oxidation of the primary alcohol.

Scheme 22. Dihydroxylation and completion of the tricyclic framework.

Until this point already 23 steps were necessary, but this process required five

chromatographic steps only, providing a nice possibility to assemble material in 11% overall

yield to this point in multiple gram quantities. After MOM deprotection the acetonide 89 was

formed stabilizing the already complex system.

The next target was the modification of the cyclopentane ring. Kinetic enolisation of 89

followed by oxidation from the less hindered concave face provided α-siloxy-ketone 91

(Scheme 23).

Introduction

27

HH

OR

OR

O

OROO

OHH

O

OR

O

OROO

O OR

Dimethyldioxirane,acetone

R = TMS

HH

OR

OR

O

OROO

O OR

TMSCl,NEt3

H

O

OR

O

OROO

O

PhSeBr

TMSCl,NEt3

HH

HH

89

90 91

92 96

88% 99%

90% 94%

H

H

OTMS

OSePh

H

H

OTMSSe+

Ph

-O

H

OTMS

93 94 95

Scheme 23. Synthesis of conjugated ketone by selenium elimination.

Again, enolisation, this time to the opposite side, afforded highly functionalized 92, the

starting point for a complex unanticipated catalytic selenium reaction. The opening step in

this sequence is supposed to be a selenation of the TMS protected secondary alcohol 92,

because this seems to be the least hindered position. Subsequent 2,3-sigmatropic

rearrangement affords a selenoxide 94 which is able to undergo syn-elimination in direction

towards the 7-memberd ringsystem. Hydrolysis of the resulting enolether 95 releases the

conjugated ketone 96.

To complete the synthesis Ley and co-workers still had to set the last stereocenter in the

cyclopentane ring of 96 by stereoselective reduction (4:1 selectivity, again by steric controlled

attack from the concave face). Esterification with angelic acid of the resulting alcohol and

removal of the TMS protecting groups afforded the diol 97 (Scheme 24). Selective acetyl

protection of the more reactive hydroxy group via a polymer supported reagent installed the

second ester group in 98.

Introduction

28

H

O

OH

O

OHOO

O

1. NaBH42. angelic acid, NEt3,

trichlorobenzoylchloride

O3. TBAF

1. isoprenylacetate,polymer-supported-TsOH

R =

O

Nortrilobolide 72%O

Trilobolide 78%O

Thapsivillosin F 73%

R2O,DMAP H

O

OAc

O

ROHOHO

OOH

H

O

OAc

O

HOHOHO

OOH

H96

97

98 99

65% 68%2. HCl (aq.), MeOH

4 4

Scheme 24. Final synthetic steps towards the Thapsigargins.

Removal of the acetal protection provided the triol 98. Esterification of the more reactive

secondary alcohol on the C-4 position finally afforded three members of the Thapsigargin

family.

1.5 Hemi-Synthesis starting from Santonin

First isolated by Kahler et al. in 1830 [84,85] it was a long and exciting way to elucidate the full

structure of (-)-α-Santonin (100).[85-90] Commercially available by extraction,[91] this

eudesmanolide provides a perfect starting point for the synthesis of various sesquiterpene

lactones (Scheme 25). Abe et al.[92-94] and Marshall et al.[95] also succeeded in the total

synthesis starting from a hexahydronaphtalene skeleton or 3-methyl-benzoic acid,

respectively.

Introduction

29

Scheme 25. Structure and rearrangement of (-)-α-Santonin (100).

Despite its own biological activity, the most important feature of (-)-α-Santonin (100) is the

possibility to rearrange the 6,6,5-eudesmanolide skeleton to a hydroazulene carbon backbone

(Scheme 25). The light induced rearrangement of 100 is one of the longest known

photochemical organic reactions.[96] The cross conjugated dienone rearranges upon irradiation

in the presence of acetic acid towards acetyl-isophotosantonic lactone 101 and serves as a

classic example for photochemical rearrangements, although it was a long way to completely

understand this reaction.[85,96-99] Furthermore was found that solvolysis of methanesulfonates

102 also provides an entry to the 5,7,5-ringsystem of the guaianolides.

1.5.1 Syntheses by Ando et al.

Ando et al. were able to synthesize more than ten guaianolides starting from (-)-α-Santonin

(100). Preparing suitable derivatives of this available natural product and subsequent

solvolytic rearrangement offers a very interesting and efficient entry towards the guaianolides.

1.5.2 Synthesis of (+)-Arborescin

(+)-Arborescin (107) was first isolated by Meisels and Weizmann from Artemisia arboresces

(Compositae), a plant used for contraceptive purpose by the ancient Greeks and Arabs.[100]

The proposed structure by Herout et al.[101] was later on confirmed by X-ray analysis.[102]

Introduction

30

In an opening step Ando et al.[103] transformed (-)-α-Santonin (100) into the eudesmanolide

103 (Scheme 26). Protecting group transformation and reduction afforded the alcohol 104.

mCPBA

OO O

OH

OH

1. BzCl2. H3O+

3. Zn(BH4)2

50%

O

OBz

HO

1. MsCl

2. AcOK63%

22%O

OBz

HO

O

O

HO

O1. K2CO3 / H2O2. MsCl

3. Li2CO3 / LiBr(+)-Arborescin (107)

31%

H

H OO

OHH

OBz

H

H

H

H

H

H

H

H

103 104

105 106

100

Scheme 26. Synthesis of (+)-Arborescin (107).

Mesylation and solvolytic rearrangement resulted in a mixture of olefins 105, which was

rectified by selective epoxidation of the tetrasubstituted double bond of the endo-isomer. The

approach of the epoxidizing agent from the sterically less hindered down face sets the right

stereochemistry for the epoxide. Subsequent deprotection and elimination afforded

(+)-Arborescin (107) with a trans annulation of the cyclopentane ring.

1.5.3 Synthesis of Zaluzanines

A similar approach was used for the synthesis of different Zaluzanines (111).[104,105] These

guaianolides were originally isolated from Zaluzania augusta and Zaluzania triloba[106,107]

and show high biological activities for example in tumor inhibition.[108]

The rearrangement of the (-)-α-Santonin (100) derivative 108 to the guaianolide skeleton 109

resulted again in a mixture of double bond isomers which was rectified by selective

epoxidation of the endo-isomer (Scheme 27).

Introduction

31

OO

O

OMsH

PPh3, DEAD,AcOH

O

OR

HO

H

111R = H Zaluzanin CR = Ac Zaluzanin D

100 O

OH

HO

H1. KOAc2. K2CO3

O

OAc

HO

H

46%

44%

3 steps

H

H

H

H

H

H

H

H

108 109

110

Scheme 27. Synthesis of (+)-Zaluzanin C/D (111).

Subsequent Mitsunobu-inversion of the secondary alcohol in 109 sets the right

stereochemistry of the hydroxygroup in the cyclopentane ring of 110 and afforded after

introduction of the exo-methylenic bond (+)-Zaluzanin C and D (111).

1.5.4 Mokko lactone, Dehydocostus Lactone and Eremanthin

Mokko Lactone (114) and Dehydrocostus Lactone (2) (both isolated from costus root

(mokko)[109,110]) and Eremanthin (5) (isolated from the hartwood oils of Eremanthus

elaeagnus and Vanillosmopsis erytrhoppa)[111-113] are also accessible via this route. A

common feature of these three natural products is the lacking of the hydroxy functionality in

the cyclopentane ring.

Starting again from (-)-α-Santonin (100) Ando and co-workers synthesized 112 (Scheme 28).

After deprotection of the ketal and double bond isomerization the resulting ketone was

reduced to the secondary alcohol 113, which is needed for subsequent mesylation. Solvolysis

directly affords Mokko Lacone (114) accompanied with its double bond isomers 115 and 116.

Desaturation of 114 and 115 releases Dehydrocostus Lactone (2) and Eremanthin (5),

respectively

Introduction

32

O

HO

O

O

1. AcOH / H2O2. Br23. Zn-Hg4. LiAl(OtBu)3H

40%

O

H OHO 6:1

1. MsCl

2. KOAc OHH

O

Mokko Lactone(114)

+ +

81%

Dehydrocostus Lactone(2)

Eremanthin(5)

1. LDA, (PhSe)22. H2O2

H

H H

H100

H

H OHH

O

H

H O

HO

H

H

OHH

O

H

H OHH

O

H

H

112 113

115 116

Scheme 28. Further Guaianolides starting from (-)-Santonin (98).

This strategy allowed Ando et al. to succeed in the total synthesis of over ten different

guaianolides (Figure 4).[114]

OH

OH

H

OHH

OH

H

Dehydrocostus LactoneIsodehydrocostus Lactone

OHH

OH

H

O

2-Oxodesoxyligustrin

OH

OH

H

O

LeucodinDehydroleucodin

OH

OH

H

O

Ludartin11 ,13-Dihydroludartin

OOHH

OH

H

8-Deoxy-11 ,13-dihydrorupicolin B

Kauniolide11 ,13-Dihydrokauniolide

Figure 4. Some guaianolides prepared by Ando and co-worker.

Introduction

33

Inspired by this route Pedro et al. were also able to present stereoselective hemi-syntheses for

(+)-11βH,13-Dihydroestafiatin, (+)-11βH,13-Dihydroludartin, (-)-Compressanolide (44), and

(-)-11βH,13-Dihydro-micheliolide starting from (-)-α-Santonin (100).[115]

1.5.5 Biomimetic synthesis of Absinthin

Several short biomimetic syntheses of several guaianolides starting from suitable modified

natural germacranolides have also been reported in literature.[47,49,51,52] The main problems

within these approaches are the insufficient availability of the staring materials or the

frequently observed complex mixtures during the cyclization reactions in combination with

poor yields. For example Gallicin (117) a germacranolide isolated from Artemisia maritima

gallica ssp Willd can be mesylated and subsequent cyclization affords the guaianolide

skeleton which can be further converted into Compressanolide (44) (Scheme 29).

Scheme 29. Biomimetic cyclization of germacranolides.

Isolated in 1953 by Herout et al.[116-118] as a main dimeric guaianolide from Artemisia

absinthium L. the complex structure of (+)-Absinthin (122) was not determined before the

1980s.[119-122] The challenging structure and the biological activity of this compound inspired

Zhang and co-workers to search for a synthetic approach towards this compound.[123]

Photochemical rearrangement of (-)-α-Santonin (100) provided access to the guaianolide

skeleton and reduction yielded the alcohol 118 (Scheme 30). Subsequent Mitsunobu-

arylselenation followed by oxidative elimination afforded the precursor diene 119.

Introduction

34

HOAc, h

NaBH4 OO

H

OAcH

OH

ArSeCN, PBu3

OOH

OAcH

NaIO4

1. neat, 10 d

O

O

HHO

H O

O

H

OH

HH

HH

H2. KOH

H

H

[4+2]Cycloaddition

HH100

39% 48%

72%

118 119

120

1. SOCl2, NEt32. OsO4, NMO MeLi

(+)-Absinthin (122)(18.6% overall)

O

O

H

O

O

H

HH

H

OO

H H O

O

H

H O

O

H

H

HH

H

HOOH

77%89%

121

3. NaIO4

Scheme 30. Biomimetic dimerisation via [4+2] Cycloaddition.

The biomimetic dimerisation of the two identical Diels-Alder partners proceeded highly

regio- and stereospecific towards 120. This can be explained by minimizing the steric

interactions during the approach of the reaction partners via the less hindered face (for the

cyclopentadiene moieties). A head to head orientation (for the lactone moieties) also

minimizes steric interactions between the 7-membered ring systems (inset box in Scheme 30).

After basic cleavage of the acetyl-protecting groups the stereocenters of the resulting tertiary

alcohol 120 had to be inverted. This was achieved by initial elimination and subsequent

oxidative cleavage of the resulting exo-cyclic double bond to release diketone 121. To

complete this biomimetic total synthesis of (+)-Absinthin (122), stereoselective methylation

of the carbonyl groups afforded the target compound in 18.6% overall yield.

Introduction

35

1.6 Conclusions

The search for new synthetic ways towards the guaianolides did not only result in new total

synthesis of complex and biological active natural products, but also contributed to the

development of a wide range of new and modern chemistry. The fundamental and

methodological aspects of natural product synthesis have always proven to be of great

importance beside the straight forward synthetic pathway towards the target structures. As

there are more and more members of the guaianolide family discovered and extracted from

different plants, the full evaluation of their biological activity is still of current interest.

Therefore total synthesis has to find new, efficient and flexible ways to make these

compounds and their derivatives available.

Aim of this work

36

2. Aim of this work This work seeks to explore a new synthetic strategy towards the total synthesis of two

interesting members of the guaianolide family, namely Cynaropicrin (123) and Ixerin Y

(126). A highly promising biological activity in combination with their complex structure

makes these compounds challenging targets for total synthesis.

2.1 Cynaropicrin - the herb principle of artichoke

The artichoke (Cynara scolymus L.) was elected as the medical plant of the year 2003.[124]

This 1.5-2 m tall perennial thistle is originated in southern Europe especially around

Mediterranean (Figure 5).[125-129]

Figure 5. Pictures of Cynara scolymus L. and structure of Cynaropicrin (123).

Dried or fresh leaves and stems of Cynara are used as a choleretic (to increase bile

production) and to treat gallstones. Furthermore, drugs are prepared from the extracts for the

treatment of dyslipidemias, arteriosclerosis and inflammatory bowel disorders.[130]

Responsible for the bitter taste of this vegetable is the guaianolide Cynaropicrin (123),[131,132]

also identified as the active principle, which shows a broad variety of biological activities:

Significant cytotoxicity against human tumor cell lines (ED50 = 0.23-1.72 µg/ml) was found

by Choi and co-worker.[133] Further reports are provided in literature on the pro-apoptotic

activity of Cynaropicrin (123) on leukocyte cancer cell lines[134] in combination with activity

in acute and chronic inflammatory processes.[135-137] In addition to this, antibacterial effects

are seen by irreversible inhibition of MurA, an enzyme responsible for the first step in

cytoplasmatic biosynthesis of peptidoglycan precursors.[138] This enzyme is of certain interest

for drug development projects, since the MurA-dependent metabolites are of vital importance

for bacteria.[139-141]

Aim of this work

37

2.2 Ixerin Y - a guaianolide sesquiterpene lactone glucoside

Various interesting natural products have been isolated from Ixeris plants (Figure 6), and

sesquiterpene lactones as the Ixerins A-Z have been characterized (Figure 7).[142-146]

Figure 6. Pictures of Ixeris denticulata f. pinnatiparita.

A wide spectrum of biological activities, such as cytotoxicity[147] as well as having ant

repellent[148] and antifeedant[149] properties is reported for some members of the Ixerin family.

In addition to this, Ixerin Y (126) shows a promising inhibitory effect against the growth of

human breast cancer cell lines (MCF7: IC50 = 6.36 µg/ml, MDA468: IC50 = 11.87 µg/ml).[57]

Prominent members of the Ixerin guaianolide family are given in Figure 7.

OOH

Ixerin Z (127)

H

H

O- -D-Glc

OOO

H

H

HO

H

Glc- -D-O

Ixerinoside (128)

OO

R

H

H

H

O- -D-Glc

125 R = -OH Ixerin X126 R = -OH Ixerin Y

OOH

H

H

O- -D-Glc

H

OH

Ixerin D (124)

4

Figure 7. Prominent members of the Ixerin guaianolide family.

A common feature of the mentioned members of the Ixerins is the glycosidic linkage of a

glucose moiety found at different positions on the hydroazulene core skeleton. Ixerin X (125)

and Y (126) differ only in the configuration of the hydroxy functionality at the C4-position

which is absent in Ixerin D (124) and Z (127).

Aim of this work

38

Table 1. Sources of members of the Ixerin family.

Entry Guaianolide isolated from Ref.

1 Ixerin D (124) Ixeris tamagawaensis [143]

2 Ixerin X (125) Ixeris Denticulata f. pinnatipartita and

Ixeris sonchifolia resp.

[57,150,151]

3 Ixerin Y (126) Ixeris Denticulata f. pinnatipartita and

Ixeris sonchifolia resp.

[57,150]

4 Ixerin Z (127) Ixeris Denticulata f. pinnatipartita and

Ixeris sonchifolia resp.

[150,152]

5 Ixerinoside (128) Ixeris sonchifolia [153]

The complex structure in combination with their broad spectrum of biological activity makes

all these compounds to challenging targets for total synthesis.

2.3 Retrosynthetic analysis of the target compounds

All total synthetic approaches described so far (see introduction) find their first target in the

construction of the guaiane core system. Once this skeleton is assembled, the trans-annulated

lactone moiety is introduced in the synthesis. The stereochemistry is mostly substrate

controlled via the hydroazulene core system and the target structures are finally reached by

functional group transformations.

In contrast to this, the synthetic approach towards the two guaianolides described above seeks

for a different route: The lactone moiety and its trans-substitution pattern is constructed first

as seen in lactone aldehyde 129, and the guaianolide skeleton is finalized by closing the

hydroazulene substructure (Figure 8).

Although Cynaropicrin (123) and Ixerin Y (126) have been isolated from very different

sources, there seems to exist quite an interesting structural relationship between these

compounds: The basic framework of 123 and 126 differs only in the position of the double

bonds within the guaiane skeleton as well as in the position of the hydroxy group on the

allylic moiety in the cyclopentane ring.

Aim of this work

39

Cynaropicrin (123)

OO

H H

RO

OH

OO

HO

O- -D-Glc

H

R= OH

O

Mannichallylation

ring closingmetathesis

OO

CHOHX

OPgSiMe2R

H

H

+

E = CO2Me

129 X = O, CH2R = Ph, OiPr

(-)-130

OPgSiMe2R

X

132 X = O, CH2R = Ph, OiPr

Ixerin Y (126)

H

H

H

H

Mannichallylationradicalcyclization

TMS

O E

O

OPg

CO2Et

CHOE(O)CO

131

133

Figure 8. Retrosynthesis of Cynaropicrin (123) and Ixerin Y (126).

Because of this, a stereoselective synthesis of both natural products is envisioned to the

common precursor 129 using either a radical cyclization or ring closing metathesis approach

to form the central seven membered ring.

The lactone aldehyde intermediate 129 having already incorporated five stereocenters with

respect to the target structures, was envisaged to be assembled from the cyclopropyl-

carbaldehyde (-)-130, accesible from furan 131, and the disubstituted allylsilane 132. The

construction of the latter is acchieved starting from the enantiomerically pure protected

cyclopentenon 133.

Main Part

40

3. Synthesis of chiral allylsilanes Allylsilanes have proven to be versatile tools in organic chemistry, especially for the mild and

highly selective Hosomi-Sakurai allylation.[154-158] To construct the southern cyclopentane

ring of the guaianolides, two chiral allylsilanes with all the desired substituents in place were

prepared. Compounds 134 and 135 are envisioned as important key intermediates with three

major features (Figure 9):

i) the allylsilane moiety allows the smooth addition onto the cyclopropylcarbaldehyde.

ii) the protected alcohol already possesses the right stereochemistry (with respect to

Cynaropicrin (123)) and can be further functionalized.

iii) the bulky silyl group in the sidechain acts as a directing group during the addition

reaction and can be transformed into a free hydroxy functionality later on.

OPgSiMe2R

TMS

134 R = Ph135 R = OiPr

O

OPg

OOH

Furfuryl alcohol(136)

133

allylic system(i)

stereocontroland

functionalization(iii)

functionalization(ii)

Figure 9. Retrosynthesis of chiral allylsilanes 134 and 135, respectively.

To be able to introduce all of these features, the synthesis of the allylsilanes 134 and 135 is

referred to the chiral protected cyclopentenone 133, which is readily accessible in

enantiomeric pure form, starting from inexpensive commercially available furfuryl

alcohol (136).

Main Part

41

3.1 Synthesis of the enantiomeric pure cyclopentenone

There are quite a number of methods known for the synthesis of optically active cis-2-

cyclopenten-1,4-diol derivatives,[159-168] but many of these show certain inconveniences

(e.g. cracking of dimer when starting from cyclopentadiene, instability of intermediates, loss

of stereoselectivity during the synthesis).[169] To avoid these problems it was decided to

follow a well established route reported by Curran et al. for large quantity preparation of

optically active cis-2-cyclopenten-1,4-diols.[169,170]

First, furfuryl alcohol (136) was rearranged to 4-hydroxycyclopent-2-enone (±)-137 in

moderate yield (Scheme 31).

Scheme 31. Synthesis of precursor for enzymatic resolution: a) KH2PO4, pH = 4.1, H2O, reflux, 2 d, 40%; b) TBDMSCl (1.15 eq.), NEt3 (1.50 eq.), DMAP (5 mol%), THF, 0 °C - rt, 89%; c) LiAlH4 (0.70 eq.), LiI (0.50 eq.), toluene/TBME, -30 °C, 3 h, 85% (cis/trans 92:8).

The following TBDMS-protection of the free hydroxy group introduces a bulky substituent in

(±)-138, which directs the subsequent reduction towards the cis-substituted (±)-139 in good

yield and selectivity.

The racemate of (±)-139 was subjected to kinetic enzymatic resolution using porcine pancreas

lipase (PPLE).[171] (-)-139 and (+)-140 were separated afterwards by simple chromatography

on silica gel, and both compounds can be used in the further synthesis providing the important

feature not to loose material within this early stage (Scheme 32).

Scheme 32. Enzymatic resolution: a) porcine pancreas lipase PPLE, vinylacetate (4.50 eq.), NEt3 (0.68 eq.), TBME, rt, 48 h, (-)-139 (95%, 92% ee), (+)-140 (80%, >99% ee).

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42

The progress in the enzymatic resolution can easily be monitored via chiral GC analysis by

determination of the ee-value for the starting material (-)-139 (Figure 10).

Figure 10. Kinetic resolution of (-)-139 monitored by chiral GC.

In the first 12 h the reaction velocity was high, illustrated in the steep slope of the curve at the

beginning (Figure 10). The maximum ee of 92% for (-)-139 was reached after 48 h. A change

of the high ee-value of >99% for the acetylated product (+)-140 was not observed during this

reaction. All attempts to recycle the used enzyme for further resolution reactions were not

successful and only very low conversion was seen.

For the further synthesis, the acetyl-protection of (+)-140 was removed by saponification

using LiOH (Scheme 33).

OR

OTBDMS

OPMB

OTBDMS

a

b c

OPMB

OH

(+)-140: R = Ac(+)-139: R = H

OPMB

OH

=

(+)-141 (-)-142

Scheme 33. a) LiOH (1.20 eq.) THF:MeOH:H2O (3:1:1), rt, 2 h, 96%; b) NaH (1.25 eq.), NaI (1.00 eq.), p-methoxybenzylbromide (1.30 eq.), THF, rt, 5 h, 86%; c) TBAF (1.00 eq.), NEt3 (0.10 eq.), THF, rt, 24 h, 85%.

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48t [h]

% ee

for (-)-139

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43

Because TBDMS- and benzyl-protection approaches already failed in previous attempts

within similar syntheses of guaianolides carried out in our group,[172] the strategy within this

work was changed to the protecting group p-methoxybenzyl (PMB) which is stable to all

conditions needed in the further synthesis and is readily removed under mild oxidative

conditions (preferably DDQ). Protection of (+)-139 by p-methoxybenzylbromide afforded

PMB-protected (+)-141 in 86% yield and standard TBDMS removal by TBAF led to (-)-142.

(-)-142 is also accessible by protecting group transformation starting from (-)-139. Reacting

the free hydroxy functionality in (-)-139 with acetic anhydride in pyridine afforded the fully

protected compound (-)-140 in excellent yield (Scheme 34).

OR

OTBDMS

OAc

OH

c

OPMB

OAc

(-)-139: R = H(-)-140: R = Ac a

b d

OPMB

OH

(+)-143 (-)-142(+)-144

Scheme 34. a) pyridine (15.0 eq.), Ac2O (4.5 eq.), rt, 6 h, 97%; b) TBAF (1.0 eq), NEt3 (0.1 eq.), THF, rt, 2 h, 95%; c) p-methoxybenzyltrichloroacetimidate (1.67 eq.), Cu(OTf)2 (5 mol%), CH2Cl2, 0 °C - rt, 24 h, 83%; d) LiOH (1.2 eq.), THF/MeOH/H2O (3:1:1), rt, 2 h, 92%.

The removal of the TBDMS protection under standard conditions smoothly provided (+)-143

as a colorless solid, which can be easily recrystallized from diethylether.

The introduction of the required PMB protecting group proved to be difficult on this

substrate. First attempts using PMB-Br (similar to the synthesis of (+)-141, Scheme 33) failed

due to racemization under these conditions. However, applying the trichloroacetimidate

protocol under Cu(OTf)2 catalysis as described by Basu et al.[173] afforded (+)-144 in good

yield and purity. Removal of the acetyl protection by standard saponification also provided

(-)-142 in 92% yield.

Altogether, both compounds resulting from the enzymatic resolution can be transformed into

the same intermediate (-)-142, providing the important possibility to assemble large quantities

of this material on this early stage of synthesis.

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44

Final oxidation of (-)-142 using PCC yielded the PMB-protected cyclopentenone (-)-145

(Scheme 35).

Scheme 35. Oxidation of (-)-142 to key intermediate (-)-145: a) PCC (1.2 eq.), 4 Å MS, CH2Cl2, rt, 24 h, 86%.

With this synthesis the key intermediate (-)-145 was accessible in 8-9 steps starting from

commercially available furfuryl alcohol (136). Each step in the described sequence was a spot

to spot reaction and could easily be monitored by TLC or GC. After optimization of the

reaction conditions, up-scaling to 18 g batches in the enzymatic resolution was possible

without loosing the enantiomeric purity of the resulting products.

3.2 Synthesis of the chiral allylsilanes

The PMB-protected cyclopentenone (-)-145 was subjected to a highly selective 1,4-addition

with appropriate cuprate reagents to introduce the functionalized carbon side chain at

C3-position.

The desired hydroxy functionality is introduced in this step, masked as a bulky silyl group,

offering certain advantages (Scheme 36): The desired cuprate reagents 147 with an n-electron

donor atom (here oxygen) attached to the metalated carbon are not readily accessible from the

corresponding halides 146 by usual procedures[174] and often involve multiple steps in their

preparation (e.g. using tin-containing intermediates).[174,175]

Scheme 36. Metal organyls used for 1,4-addition: a) Mg (3.0 eq.), THF, rt, 2 h.

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45

Additionally, the introduction of a further hydroxy protecting group at this early stage of the

synthesis was thought to be problematic in terms of restrictions in transformations and in

protecting group differentiation.

To avoid these problems, commercially available chloromethylsilanes 148 (R = OiPr, Ph)

were used for standard Grignard formation. In situ conversion to the appropriate cuprates

provided the reagents for the 1,4-addition onto cyclopentenone (-)-145. The use of different

substituents at the silicon atom (R = OiPr, Ph) opens the possibility to investigate different

conversion protocols for the transformation of the masked hydroxy group into the

corresponding free alcohol.

Because the bulky PMB-protecting group in (-)-145 shields the lower half space, the cuprate

addition proceeds highly diastereoselectively from the upper face resulting in the desired anti-

substitution on the cyclopentane ring. The resulting enolates were trapped in the presence of

TMS-Cl as the corresponding silylenolethers 150 and 151 (Scheme 37). These materials are

very sensitive to heat and traces of acid.[176] Therefore, purification by distillation or

chromatography was not possible, however, after extensive extraction the products possessed

sufficient purity to carry on with the next steps.

OPMB

O

SiMe2R

TMS

OPMBSiMe2

R

TMS

a b(-)-145

150 R = Ph151 R = OiPr

152 R = Ph153 R = OiPr

Scheme 37. Synthesis of chiral allylsilanes: a) LiCl (0.3 eq.), CuI (0.15 eq.), TMSCl (4.0 eq.), R = Ph: PhMe2SiCH2MgCl (1N in THF) (1.25 eq.), THF, -78 °C, 3 h, 99%, dr >99:1; R = OiPr: iPrOMe2SiCH2MgCl (1 N in THF) (1.15 eq.), THF, -78 °C, 3 h, 90%, dr >99:1; b) Ni(acac)2 (0.1-1.0 eq.) Me3SiCH2MgCl (1 N in Et2O) (1.5-2.0 eq.), Et2O, rt, 5 d, R = Ph: 40%, R = OiPr: 34%.

For the final transformation of the silylenolethers into the corresponding allylsilanes 152 and

153 a modified procedure reported by Kumada et al. was used.[177] Ni(acac)2 catalyzes the

coupling of silylenolethers with the appropriate Grignard reagent to afford the desired

allylsilanes 152-153 only in moderate yields (34-40%). This might be due to the highly

substituted cyclopentane ring and the resulting steric strain preventing the cross coupling to

the allylsilanes. Attempts to improve this reaction by gentle warming, elongated reaction

times or increasing the catalyst loading as well as reagent excess did not lead to better results.

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46

From the Ni(acac)2 coupling reaction compounds 154 and 155 were also isolated as

decomposition products of the corresponding silylenolether (Scheme 38).

Scheme 38. Possible use of by-products.

These trans-substituted cyclopentenones 154 and 155 are very interesting structures

themselves, since sugar-like trisubstituted cyclopentanes 157 and 158 could become

accessible within a short sequence, including Tamao-Fleming oxidation of the side chain and

reduction of the resulting ketone 156. These pseudo-anomeric structures have already proven

to be important compounds as sugar mimics for pharmaceutical or biochemical purposes.[178]

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47

4. Synthesis of the cyclopropylcarbaldehyde Both enantiomers of the highly functionalized 1,2,3-trisubstituted cyclopropylcarbaldehyde

130 are readily accessible in enantiomeric pure form via a well established two step sequence

starting from methyl-2-furoate (131).[6,74,179,180]

The stereochemical outcome of the sequence of cyclopropanation, ozonolysis to the

cyclopropylcarbaldehyde 130 and subsequent allylation/retroaldol-lactonization depends on

the stereochemistry of the bis(oxazoline)-ligand (BOX) 159 initially used (Figure 11 and

Scheme 39).

Figure 11. iPr-BOX-ligands (+)/(-)-159 used for asymmetric cyclopropanation.

Scheme 39. Stereochemical relationships of iPr-BOX-ligands and stereochemistry of lactone aldehydes.

The (R,R)-iPr-BOX ligand (+)-159 derived from D-valine leads to the desired substitution

pattern on the lactone aldehyde 161 as found in the natural products, and subsequently the

(S,S)-iPr-BOX ligand (-)-159, prepared from the less expensive natural L-valine, gives rise to

the enantiomeric compound 162.

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48

Both enantiomers of the chiral BOX-ligands 159 were prepared starting from D- or L-valinol

164, derived from the corresponding amino acids by reduction with sodiumborohydride and

iodine. Coupling of 2,2-dimethylpropane-dioyl-dichloride 163 and valinol 164 proceeded

successfully to diamide 165 (Scheme 40). Subsequent tosylation and cyclization gives rise to

the corresponding enantiomeric pure ligand (+)-159.[181]

Scheme 40. Synthesis of bis(4-isopropyloxazoline) ligand: a) valinol (2.0 eq.), NEt3 (2.5 eq.), CH2Cl2, 0-rt °C, 70 min, 84%; b) DMAP (10 mol%), NEt3 (4.0 eq.), TsCl (2.0 eq.), CH2Cl2, rt, 27 h, 83%.

BOX-ligand (+)-159 was applied in a Cu(I)-mediated asymmetric regio- and

diastereoselective cyclopropanation of methyl-2-furoate (131), resulting in (+)-160 with high

enantioselectivity of 85-90% ee, which was improved to >99% ee after recrystallization

(Scheme 41).

Scheme 41. Cyclopropanation and ozonolysis: a) (i) ethyl diazoacetate (2.67 eq.), Cu(OTf)2 (0.66 mol%), (+)-159 (0.84 mol%), PhNHNH2 (0.70 mol%), CH2Cl2, 0 °C, 54%, 85-90% ee; (ii) recrystallization (CH2Cl2, pentane), >99% ee, 37%; b) (i) O3, CH2Cl2, -78 °C; (ii) DMS (4.00 eq.), 22 h, -78 °C - rt, 90%.

The stereochemical outcome of this reaction can be explained applying the models suggested

by Pfaltz[182] and Andersson[183] for the asymmetric cyclopropanation of alkenes:

The reactive complex 166 in this reaction is shown in Figure 12 (left). An approach of 131

(substituent CO2Me oriented away from 166 to minimize steric interactions) from the right

side is expected to be favored, since an attack from the left side shows strong repulsive steric

interaction of the approaching olefin 131 and the iPr group of the ligand (+)-159 (Figure 12,

right). An attack from the right side will also lead to a flipping of the ester group E in 166 to

the left (counterclockwise), resulting in only small interactions with the hydrogen

substituent Ha.

Main Part

49

Figure 12. Reactive complex and model for asymmetric cyclopropanation.

In the subsequent cyclopropanation the less substituted and presumably more electron rich

double bond of 131 is attacked.

The formation of the corresponding endo-diastereomer was not observed and after

optimization of the reaction conditions a scale-up to 50-100 g was possible, still affording

high enantioselectivity, so that both enantiomers of 160 can be prepared in optical pure form

and multigram quantities.

To access the cyclopropylcarbaldehyde, the double bond present in (+)-160 was cleaved by

ozonolysis followed by reductive work-up leading to (+)-130 in 90% yield (Scheme 41). This

material rendered solid upon treatment with diethylether and was stable for months while

stored under a nitrogen atmosphere at -35 °C.

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50

5. Formation of the anti-substituted lactone aldehyde The next step was the addition of the chiral allylsilanes to the cyclopropylcarbaldehyde. In

general, the stereocontrol of additions onto a cyclopropyl-substituted carbonyl compound 167

can be explained by analyzing the conformational preferences and applying the Felkin-Anh-

model[184] in combination with the Curtin-Hammett-principle.[185]

The cyclopropane ring shows in analogy to an alkene double bond strong π-donating

properties. These are only effective in the two bisected conformations, which are very similar

to the Felkin-Anh conformations s-cis-167 and s-trans-167 of the cyclopropyl-substituted

carbonyl compounds (Scheme 42).

OH

H

OR

CO2EtH

H

Nu

(s-cis)-167 (s-trans)-167

Nu

OH

CO2Et

RO

anti-Felkin-Anh-168

Nu

OH

CO2Et

RO

Felkin-Anh-168

O H

H

OR

CO2EtH

H

R = C(O)CO2MeNu

Scheme 42. Nucleophilic attack on cyclopropyl-substituted carbonyl compounds.

From these possible conformations the latter is energetically more favored because the steric

interactions of the aldehyde and the space demanding cyclopropane ring are minimized. A

nucleophile attacking the more stable s-trans-167 conformation would consequently have to

approach over a bulky substituent leading to the anti-Felkin-Anh-168 product. The

experimentally observed Felkin-Anh-168 product results from the s-cis-167 conformation

which is attacked by the nucleophile coming over a less hindered half space.

If the activation energies of the selectivity determining step are higher than the rotation barrier

between the different conformers, the Curtin-Hammet principle can be applied. For this case

not the preferred conformation of the substrate (here s-trans-167) is responsible for the

product distribution, but the activation energy of the transition state determines the

stereochemical outcome.

In the case described here, the rotation barrier for the transformation of s-cis to s-trans must

be smaller than the activation barrier for the selective addition step and so the attack of bulky

nucleophiles will occur on the less hindered path over the smaller substituent leading to the

experimentally observed Felkin-Anh-168 product.

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51

The synthesized chiral silylenolethers 150/151 and allylsilanes 152/153 were now combined

in a Lewis acid mediated Mukaiyama-aldol reaction or a Hosomi-Sakurai allylation with the

cyclopropylcarbaldehyde (+)-130, respectively.

All attempts to add the silylenolether 151 and allylsilane 153 with the OiPr- substituent at the

silicon atom in the side chain failed due to decomposition of the silyl precursor.

In contrast, the reactions using the Ph-substituted compounds 150 and 152 proceeded

smoothly to the highly substituted intermediates 170 and 171 which were obtained as single

diastereomers (Scheme 43). The Mukaiyama-aldol reaction of 150 (X = O) did not afford a

clean product 170, as the silylenolether could not be purified and therefore had to be used as a

crude material.

X

OPMB

CHO

HO X

OPMBSiMe2Ph

+

TMS

SiMe2Ph

R = C(O)CO2Me

170: X = O171: X = CH2

H

150: X = O152: X = CH2

a

CO2Et

CO2Et

RO

RO

(+)-130

OH

H

OR

CO2EtH

HOPMB

Me3Si

H

BF3

SiMe2Ph

169

Scheme 43. Addition of chiral silylenolethers and allylsilanes to the cyclopropylcarbaldehyde: a) BF3⋅OEt2 (1.1 eq.), CH2Cl2, -78 °C, 16 h, 170: X = O: 95%, dr >99:1; 171: X = CH2: 95%, dr >99:1.

These highly functionalized materials can not be purified easily by distillation due to their

high molecular mass or chromatography because they tend to decompose on silica gel. Simple

extraction afforded the products in sufficient purity to proceed with the next step in the

synthesis.

The stereochemical outcome of this reaction can be explained by the proposed transition state

169 (Scheme 43). In this case, the nucleophile attacks the s-cis-conformation of the carbonyl

group in anti-orientation to its bulky substituent (CH2SiMe2Ph) leading to the trans-Felkin-

Anh-products 170 and 171 (see discussion above).

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52

In an attempt to combine 152 and (-)-130 in the mismatched case, only a complex mixture of

at least four compounds was observed in a very low yield, which indicates the importance of

the double stereochemical differentiation with the chiral allylsilanes.

Upon treatment with Ba(OH)2 in methanol only the Hosomi-Sakurai allylation product 171

(X = CH2) rearranged to the lactone aldehyde 175 in 72% yield (Scheme 44). Attempts to use

triethylamine or LiOH as base for this transformation failed. The reaction proceeds by

saponification of the more labile oxalic ester, upon which a ring opening of the now

unmasked donor-acceptor substituted cyclopropane 172 is triggered, followed by

lactonization of 173 to give 175 as a single stereoisomer.

Scheme 44. Retroaldol-lactonization: a) Ba(OH)2⋅8H2O (0.55 eq.), MeOH, rt, 2 h, 72%, dr >99:1; b) i) O3, CH2Cl2, -78 °C, 15 min; ii) DMS (4.0 eq.), -78 °C - rt, 24 h.

In contrast, the addition product 170 which resulted from the Mukaiyama-aldol reaction failed

to rearrange into the ketone-aldehyde 176. Therefore, an attempt was made to subject lactone

aldehyde 175 to ozonolysis conditions to access the ketoaldehyde 176, but only

decomposition of the starting material was observed.

The lactone aldehyde 175 is an important key-intermediate in further investigations towards

the total synthesis of guaianolide sesquiterpene lactones: The trans-stereochemistry at the

lactone ring is already set and the cyclopentane ring is highly functionalized also having the

stereochemistry at the connection point to the lactone ring and the protected hydroxy group

set in the right way. The aldehyde group and the double bond present in the molecule are

versatile functionalities, which allow many further transformations to construct the framework

of the guaianolides and related natural products via certain ring closing reactions.

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53

6. Investigations towards 5,6,5-ring systems In addition to oxidative derivatisation, nature has also the possibility to rearrange the complex

5,7,5-carbon skeleton of the guaianolides. Probably by a Wagner-Meerwein-type

rearrangement a 5,6,5-ring system is formed, as for example found in Lasiolaenolide (178)

and its derivatives, isolated from various plants, such as Lasiolaena santosii (Scheme 45).[186]

Scheme 45. Ring closing reactions to form rearranged guaianolides.

The lactone-aldehyde 175 should be a suitable precursor to construct the core 177 of this

family of natural products. Connecting the carbonyl-carbon with the opposite double bond

would lead to a 5,6,5-ring system. Although, the methyl group at the C5-position is lacking

this transformation would provide a direct and interesting route to this skeleton.

6.1 Intramolecular carbonyl-ene reaction

The first approach to perform this ring closure was the utilization of an intramolecular

carbonyl-ene reaction on aldehyde 175 which should directly lead to the 5,6,5-membered ring

system 179 (Scheme 46).

Scheme 46. Intramolecular carbonyl-en-reaction: a) see Table 2.

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54

Although intramolecular carbonyl-ene reactions on less functionalized precursors have been

reported,[187] treating lactone aldehyde 175 with different Lewis acids at different

temperatures did not lead to the desired tricyclic structure 179 (Table 2). At low temperatures

(-78 °C) no reaction was observed and at higher temperature (0 °C or rt) only decomposition

of the starting material occurred.

Table 2. Intramolecular carbonyl-ene-reaction conditions.

Entry Lewis Acid Reaction conditions Yield

1 BF3⋅OEt2 (2.0 eq.) -78 °C, 4 h no reaction

2 BF3⋅OEt2 (2.0 eq.) rt, 4 h decomposition

3 BF3⋅OEt2 (2.0 eq.) 0 °C, 1 h decomposition

4 TiCl4 (2.0 eq.) 0 °C, 1 h decomposition

5 SnCl4 (2.0 eq.) 0 °C, 1 h decomposition

The difficulties encountered in this transformation might be due to the high functionalization

of 175 and moreover, the PMB protecting group might not be stable under these Lewis acidic

conditions.

Scheme 47. PMB deprotection of 175: a) DDQ (1.14 eq.), CH2Cl2/H2O, rt, 2 h.

To remove the PMB protecting group, 175 was treated with DDQ (Scheme 47). This resulted

in an inseparable mixture of unknown products and did not afford the desired free

alcohol 180.

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55

6.2 SmI2-promoted radical cyclization

Another potential reaction for the construction of the skeleton of type 177 is the SmI2

promoted intramolecular radical cyclization of aldehydes into C=C-double bonds which

already has found many applications in the total synthesis of various natural products.[188]

SmI2 is a one-electron-transfer reagent, which should transform the lactone aldehyde 175 into

the radical intermediate 181 (Scheme 48). Subsequent cyclization by incorporating the

exo-double bond would led to the 5,6,5-membered ring system 182. The 6-endo product

should form with preference rather than the 5-exo product, since the trans-configuration at the

lactone moiety introduces strain into the system. This should lead to the formation of the

larger ring which is presumably thermodynamically more stable. Moreover, upon the 5-exo

ring closure a primary radical rather than a tertiary radical as for the 6-endo ring closure

would be formed.

Scheme 48. SmI2-promoted radical cyclization: a) SmI2 (2.0 eq.), THF, 0 °C, 2 h.

Unfortunately, applying the standard SmI2 cyclization conditions on lactone aldehyde 175 did

not afford the expected tricyclic structure and resulted in an inseparable mixture of

undefinable products.

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56

7. Investigations towards the guaianolide core skeleton Since all previous attempts (carbonyl-ene reaction and SmI2-radical cyclization) to build a

tricyclic framework failed, the strategy was changed, focusing on the construction of the

5,7,5-membered ring system of the guaianolides. Different approaches to close the central

7-membered ring were explored including radical cyclization and ring closing metathesis.

7.1 Radical cyclization approach

We were already able to show the transformation of simplified precursors 71 into bi- and

tricyclic sesquiterpene lactone skeletons 72 via radical cyclizations (Scheme 49).[74]

Scheme 49. Synthesis of unsubstituted bi- and tricyclic sesquiterpene lactone scaffolds by radical cyclization.

This promising sequence was investigated on lactone aldehyde 175. Alkenylation by a

modified Horner-Wadsworth-Emmons (HWE) reaction gave rise to 183 in 72% yield and in

an expected preference for the Z-isomer (E/Z = 17:83). Here it has to be noted that it proved

to be more convenient and higher yielding to generate the 2-bromo-phosphonoacetate in situ

to prevent the formation of unhalogenated HWE-product.

Scheme 50. Radical cyclizations towards the guaianolide skeleton: a) (i) NaH (1.05 eq.), triethylphosphono-acetate (1.05 eq.), Br2 (1.11 eq.), THF, 0 °C, 1 h; (ii) NaH (1.05 eq.), 175, THF, 0 °C to rt, 1 h, 72%, E/Z = 17:83; b) AIBN (0.2 eq.), Bu3SnH (1.5 eq.), benzene, reflux, 2 h, 89%, dr = 87:13; c) DDQ (1.3 eq.), CH2Cl2, pH 7 buffer, rt, 4 h, 89%.

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57

Under diluted radical generating conditions (AIBN, Bu3SnH) an E/Z-mixture of 183 (17:83)

reacted to the tricyclic guaianolide scaffold 184. While comparing the remarkably high yield

(89%) of this radical cyclization with the E/Z-ratio of the precursor it is clear, that both

isomers can be cyclized.

Deprotection of the PMB-group on the finalized core skeleton under standard conditions

using DDQ gave rise to 185 in 89% yield (Scheme 50), which can be subjected to further

functionalization (e.g. oxidation, esterification, glycosylation).

Stork et al. have shown the synthetic value of vinyl radicals.[189,190] Based on this work it was

recognized, that a fast inversion of the radical species between E- and the corresponding

Z-isomer takes place. An explanation for this behavior is found in the analysis of the involved

orbitals (Scheme 51).

Scheme 51. Orbital inversion of vinyl radicals.

The orbital hybridization of 186 and 188 with a bent structure is best described as sp2-hybrids:

The unpaired electron is therefore found in a sp2-orbital and an angle of approximately 60 °

against the elongated C-C bond is included.

The transition state of the radical inversion is best represented with the linear structure 187

having a sp-hybridization and the unpaired electron located in a p-orbital perpendicular to the

π-bond. The geometry of the radical center is highly influenced by the π-(C=C)-double bond

and the σ-(C-R3)-single bond and a nearly linear assembly is assumed. Indeed, this

assumption was proven by EPR-spectroscopy (especially for R3 = CO2H or Ph)[191] and a low

inversion barrier for the interconversion of Z- and E-isomers is seen, resulting in a fast

inversion of the vinyl radical.[192,193] Therefore, both isomers can take part in the cyclization

reaction to give rise to the observed high yield of 89% in this transformation.

Main Part

58

The mechanism for the cyclization reaction of 183 to 184 appears obvious, but there are two

pathways possible, both leading to the same final product (Scheme 52):

After initial radical formation, a reaction can take place directly with the opposite double

bond present in 189 to form the observed product 184 via a 7-endo-trig cyclization.

Also, an initial 6-exo-trig cyclization of 189 towards 190 is conceivable, providing a primary

radical which can subsequently form the cyclopropinylcarbinyl radical 191. Rearrangement of

this highly strained structure leads also to the isolated 7-endo-product 184.

Although, radical trapping experiments in the presence of ethylacrylate as a possible

scavenger were tried, the exact reaction mechanism remains unknown.

Scheme 52. Possible radical cyclization mechanisms towards 184.

The stereochemistry of the final product 184 was then determined by NOE-experiments

where a clear coupling between 6a-3a, 6a-9a and 6a-CH2Si-protons is seen only for the major

isomer. This is only possible in the cis-fused case, where these protons are found on the same

side of the molecule. This preference (87:13) can be explained by a lower allover strain within

the guaianolide core by a cis-fused cyclopentane ring system, where the final H-addition

occurs from the top face of the molecule.

Main Part

59

7.2 Ring closing metathesis approach

Ring closing metathesis (RCM) is a versatile tool in organic chemistry and has already proven

t